Wu Wen-Yong, Kim Hyunchul, Zhang Chang-Le, Meng Xiang-Ling, Wu Zheng-Sheng
Department of General Surgery, First Affiliated Hospital of Anhui Medical University , Anhui, Hefei , P.R. China .
J Invest Surg. 2014 Aug;27(4):197-204. doi: 10.3109/08941939.2013.873098. Epub 2014 Jan 29.
Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. Constitutive activation of STAT3 is found in various types of tumors, including HCC. In addition, suppressors of cytokine signaling 3 (SOCS3) signals for negative feedback to STATs, and is found to be inversely correlated with STAT3 expression. However, the exact role of SOCS3 in the tumorigenesis and progression of HCC is not fully understood. In this study we intended to show that SOCS3 inhibition promotes proliferation, migration, and invasion of HCC cells. HepG2, a human HCC cell line, was grown with SOCS3 siRNA or negative control (NC) transfection to assess the involvement of SOCS3 in cell proliferation, migration, and invasion by MTT, migration, and invasion assays, respectively. Western blot analysis was performed to examine the expression of STAT3, SOCS3, c-myc, matrix metalloproteinase (MMP)-2, and MMP-9 after transfection with either SOCS3 or NC siRNAs. A diethylnitrosamine (DEN)-induced HCC mouse model was assessed with or without injection of NSC 74859, a STAT3 inhibitor, to show accompanied changes among the expressions of STAT3, SOCS3, c-myc, MMP-2, and MMP-9. Inhibition of SOCS3 expression promoted the proliferation, migration, and invasion of HepG2 cells and increased the expression of c-myc, MMP-2, and MMP-9. HCC tumors developed in mice by DEN-induction with administration of NSC 74859 resulted in decreased expression of c-myc, MMP-2, and MMP-9, but not SOCS3. Loss of SOCS3 increased tumor growth, migration, and invasion and resulted in accompanied changes in expression of STAT3 and its target oncoproteins.
肝细胞癌（HCC）是最常见的癌症之一，死亡率很高。STAT3的组成型激活在包括HCC在内的各种肿瘤类型中均有发现。此外，细胞因子信号转导抑制因子3（SOCS3）对STATs起负反馈信号作用，且发现其与STAT3表达呈负相关。然而，SOCS3在HCC肿瘤发生和进展中的确切作用尚未完全明确。在本研究中，我们旨在表明抑制SOCS3可促进HCC细胞的增殖、迁移和侵袭。将人HCC细胞系HepG2用SOCS3小干扰RNA（siRNA）或阴性对照（NC）转染，分别通过MTT法、迁移实验和侵袭实验评估SOCS3在细胞增殖、迁移和侵袭中的作用。转染SOCS3或NC siRNA后，进行蛋白质免疫印迹分析以检测STAT3、SOCS3、c-myc、基质金属蛋白酶（MMP）-2和MMP-9的表达。用二乙基亚硝胺（DEN）诱导建立HCC小鼠模型，分别注射或不注射STAT3抑制剂NSC 74859，以观察STAT3、SOCS3、c-myc、MMP-2和MMP-9表达的伴随变化。抑制SOCS3表达可促进HepG2细胞的增殖、迁移和侵袭，并增加c-myc、MMP-2和MMP-9的表达。在DEN诱导并给予NSC 74859的小鼠中发生的HCC肿瘤，导致c-myc、MMP-2和MMP-9表达降低，但SOCS3表达未降低。SOCS3缺失会增加肿瘤生长、迁移和侵袭，并导致STAT3及其靶标癌蛋白表达的伴随变化。
